Chronic Obstructive Pulmonary Disease (COPD) is major health problem with increasing prevalence and mortality. Hypotheses for the proliferation of COPD have focused on exacerbating factors such as viral infections, tobacco exposure, and air pollution. Although our understanding of the cellular and molecular mechanisms of COPD is rudimentary, considerable amounts of data now suggest a link between oxidative stress, pulmonary inflammation, and COPD. Our data, and that of others, indicate that exposure to laboratory-generated surrogate pollutant/particle systems (UFP; < 0.1 ^m diameter) increases oxidative stress in vitro and in vivo. Increasing evidence suggests that an imbalance between reactive oxygen species (ROS) and reactive nitrogen species (RNS) and the enzymes that regulate their bioavailability is associated with structural damage to the airways resulting in reduced gas exchange/blood oxygenation and thus functional damage. Our preliminary results show that our UFP initiate an inflammatory response in the lung that parallels the immuno- and patho-physiology observed in COPD. These data led us to the overall hypothesis that persistent free radical containing ultrafine pollutant/particle systems (PFR/UFP) initiate immunological changes that predispose to chronic lung diseases (CLD), such as COPD, by increasing oxidative stress and altering dendritic cell (DC) function. The following specific aims will critically address this hypothesis: 1) determine the impact of exposure to UFP in the normal lung and in the exacerbation of pulmonary immune homeostasis and pathophysiology in a disease setting (i.e. COPD); 2) characterize the impact of exposure to UFP on pulmonary DC responses; and 3) elucidate the molecular events by which UFP induces immune dysfunction and document the role of free radicals in these responses. This application represents a unique, multidisciplinary approach to characterize the role of ROS and RNS in UFPinduced pulmonary and immune dysfunction. Completion of the proposed studies will provide insight into how combustion/thermal degradation of Superfund wastes affects the development and progression of inflammatory airways disease with the expectation of valid extrapolation to human inflammatory airways disease (i.e. COPD) and should provide a rational framework for clinical studies of antioxidant usage during UFP-associated disease exacerbation. The outcome of these studies will also have important implications for public health and environmental policy, since currently there are no air quality standards for ultrafine particulates.